Date Published: January 09, 2018
Publisher: John Wiley and Sons Inc.
Author(s): Daniel A. Foyt, Michael D. A. Norman, Tracy T. L. Yu, Eileen Gentleman.
Regenerative medicine aims to tackle a panoply of challenges from repairing focal damage to articular cartilage to preventing pathological tissue remodeling after myocardial infarction. Hydrogels are water‐swollen networks formed from synthetic or naturally derived polymers and are emerging as important tools to address these challenges. Recent advances in hydrogel chemistries are enabling researchers to create hydrogels that can act as 3D ex vivo tissue models, allowing them to explore fundamental questions in cell biology by replicating tissues’ dynamic and nonlinear physical properties. Enabled by cutting edge techniques such as 3D bioprinting, cell‐laden hydrogels are also being developed with highly controlled tissue‐specific architectures, vasculature, and biological functions that together can direct tissue repair. Moreover, advanced in situ forming and acellular hydrogels are increasingly finding use as delivery vehicles for bioactive compounds and in mediating host cell response. Here, advances in the design and fabrication of hydrogels for regenerative medicine are reviewed. It is also addressed how controlled chemistries are allowing for precise engineering of spatial and time‐dependent properties in hydrogels with a look to how these materials will eventually translate to clinical applications.
Hydrogels are water‐swollen polymer networks formed by cross‐linked polymer chains and are ubiquitous in nature. The slime‐producing, eel‐like hagfish releases a mucin‐based hydrogel to choke its predators,1 and humans rely on a hydrogel network composed of collagen and hyaluronic acid (HA) to form the vitreous humor of the eye.2 However, hydrogels can also be formed from synthetic polymers, opening a myriad of synthesis strategies to create materials with widely different physical, chemical, and biological properties. Because of their hydrophilicity and chemical amenability, hydrogels have long been an exciting and promising tool in biomaterials and biomedical research. Indeed, their use in applications including as soft contact lenses for correcting vision was first proposed by Czech chemists Wichterle and Lím more than 50 years ago.3 However, the rise of the fields of drug delivery, cell therapies, and tissue engineering (TE) over the past decades has widened the scope of their potential applications and hydrogels are now being developed to do everything from repair articular cartilage damaged by osteoarthritis,4, 5 to regenerate heart tissue after myocardial infarction.6
It was not long after George Otto Gey managed to culture Henrietta Lacks’s cervical cancer cells in a dish11 that researchers realized that cells behave differently in the body than they do on tissue culture plastic.12 Many cells on 2D surfaces adopt unnatural polarities and create large focal adhesion plaques, behaviors (among a myriad others), which fundamentally differ when cells are within native tissues.12 Therefore, to fundamentally understand how cells respond in health and disease to a variety of stimuli, it is important to develop culture systems which better mimic cells’ normal 3D environments. The 3D structure and ECM‐like properties of hydrogels make them one of the best tools biologists have for doing exactly this.
In addition to developing materials that can be used as ex vivo tissue models, there is also tremendous interest in using hydrogels directly in TE. TE aims to treat a myriad of diseases by replacing lost/damaged tissue with living constructs created in the laboratory. The applications of TE range from restoring tissue lost to myocardial infarction, to filling bone defects with cell‐laden scaffolds that respond to load and remodel over time. However, the repair/regeneration of complex tissues and organs requires approaches that are specific to each tissue. When designing a hydrogel that can mediate tissue repair, several parameters are key to consider, including the tissue architecture, mechanical and biological cues, and cell type (Figure3). Indeed, advances in all three areas are likely key in ensuring effective regeneration.
As cell‐based therapies such as TE offer numerous possibilities for tissue regeneration, there is good reason for excitement surrounding their development. However, cell‐based therapies face significant challenges in terms of cost, regulatory hurdles, and scalability.95, 96 Cell free therapies, on the other hand, are often not as limited in their path to clinical translation because they tend to be less complex. Traditionally, acellular biomaterials have been used simply as fillers and for structural support, however, a new generation of acellular hydrogels are being designed to interact with endogenous factors, including local tissue and cells, to aid with healing and promote tissue regeneration (Figure8).95, 97
While researchers exploit hydrogel technologies to understand how biochemical and biophysical cues influence cell and tissue function to create 3D tissue models and TE platforms, being able to exploit these cues with hydrogels depends upon our ability to deliver them for appropriate therapeutic applications (Figure9). Simple implantation of biomaterials through traditional surgical means is a standard delivery route. However, surgery can lead to morbidity at the implantation site, is associated with surgical and recovery costs, and will almost always cause patient discomfort.127 For example, to treat osteochondral defects on the articulating surfaces of the knee, early hydrogel implants (such as Cartipatch, an alginate‐based construct) required surgery, which could cause inflammation and increased the chance of infection, which could result in treatment failure.128 To overcome these drawbacks there have been significant efforts to design injectable, in situ forming, and nano/microhydrogel systems that can be delivered in a minimally invasive manner.
The majority of the drugs and therapeutics developed for human use fail during their discovery and development stages. Indeed, only 10.4% of all candidates put through Phase I clinical trials eventually receive approval for use in humans.167 For more than 20 years now, TE‐based therapies have been proposed and pushed through the development stages toward clinical translation in the hope of creating functional tissues to replace those lost to disease or injury.168 As of July 2017, there were 371 clinical trials registered worldwide that related to hydrogels and 69 that focused on TE (www.clinicaltrials.gov). Although only a handful of these studies aimed to apply recent advances in hydrogels to TE, there have been some limited successes, particularly for planar and hollow organs, such as skin, cornea, urethra, urinary bladder, and blood vessels.169 However, the development of TE‐based regenerative strategies for more complex tissues still faces a number of key challenges.168, 170 These include: (1) provision of adequate oxygen and nutrients to large tissues, which likely require the formation of a complex vasculature; (2) incorporation of multiple cell types with precise spatial arrangements; (3) achievement of appropriate, tissue‐specific mechanical properties (such as stiffness, shear strength and hardness); and (4) integration of TE constructs with surrounding tissue. Hydrogel‐based TE scaffolds offer the possibility of addressing many of these challenges and perhaps can be successfully translated into viable therapies. We highlight some promising preclinical and clinical studies that have exploited hydrogels for TE‐based therapies below.
Over the last decade, hydrogel technologies have improved dramatically allowing researchers to create ex vivo tissue models that replicate that native tissue better than ever before. Researchers are also developing hydrogel‐based biomaterials with controlled architectures and biological and physical properties that can be used for TE. Moreover, acellular hydrogels that can deliver bioactive molecules are increasingly finding use in drug delivery applications, often relying on their injectability and chemistries that allow for in situ gelation. Taken together, the result is a toolbox of hydrogel‐based materials that can be used by both bench‐based researchers to answer fundamental questions in cell biology, and physicians to either replace damaged tissues or deliver cells/molecules to mediate repair. Indeed, the advancements in regenerative medicine that these new hydrogel technologies are likely to foster are surely something to feel “swell” about.
The authors declare no conflict of interest.